ABSTRACT The long-term goal of this proposal is to understand the shared genetic bases of psychiatric disorders to improve prevention, diagnosis, and treatment of these serious illnesses. Recent successes of large-scale genomics studies have verified extensive sharing of common variant risk across major psychiatric disorders at a genome-wide level. Nevertheless, little is known of which and how certain genetic loci carry risk effects transcending traditional diagnostic boundaries. To fill in this critical gap, we propose for the first time the systematic identification and functional characterization of genetic effects shared among eleven neuropsychiatric disorders using genome-wide SNP data on over 1 million individuals. Our central hypothesis is that there are pathogenic mechanisms shared amongst broad domains of psychiatric disorders, one of which centers on the development of the nervous system and chromatin remodeling that governs brain-specific gene expression. In support of this hypothesis, preliminary data based on eight neuropsychiatric disorders show that more than a hundred of genetic risk loci carrying significant and robust pleiotropic effects are enriched among brain-active genes critical to cell identity, cell differentiation, and transcriptional regulation. In this study, we will use genome-wide genetic data of unparalleled size and scope to achieve the following three aims with independent benefits: (1) to uncover a comprehensive spectrum of pleiotropic risk effects spanning eleven neuropsychiatric disorders; (2) to systematically evaluate the characteristics of pleiotropic risk genes; and (3) to identify biological mechanisms commonly altered by pleiotropic risk genes underlying psychopathology. Through this unique and powerful study, we expect to gain new insight into how pervasive genetic pleiotropy shapes the etiology and structure of psychopathology. This study will also produce novel analytic methods and strategies that are applicable in any cross-disorder genetics studies, providing immediate and significant impact to the research community.